Helicobacter pylori (H. pylori) infection is the most common cause of chronic gastritis. H. pylori has also been implicated as an etiological factor in the development of peptic ulcer disease. More recently epidemiological studies have demonstrated that H. pylori is an independent risk factor for gastric cancer. However, the mechanisms by which H. pylori causes epithelial cell injury, or leads to the development of peptic ulcers and gastric cancer is not well understood. People infected with H. pylori have a 3 to 9 fold higher risk of developing gastric cancer than non-infected persons. Progression from superficial gastritis caused by H. pylori to atrophic gastritis with intestinal metaplasia is felt to be a precursor to gastric cancer development. Investigators have postulated that the natural progression of H. pylori-associated chronic gastritis is to atrophic gastritis, which may be prolonged or shortened by dietary factors. Active oxygen has been implicated in gastric carcinogenesis and an antioxidant rich diet is associated with a decreased risk of gastric cancer. The hallmark of H. pylori associated gastritis is the presence of both acute and chronic inflammatory cells. H. pylori lipopolysaccharide and surface proteins both stimulate the production of superoxide anion and cytokines by monocytes. Active oxygen, produced by inflammatory cells, is known to be toxic to epithelial cells. Active oxygen compounds may also act as carcinogens, and therefore, may be partly responsible for the increased association of gastric cancer in patients infected with H. pylori. Studies outlined in this proposal will determine if exposure of gastric cells to H. pylori proteins stimulates generation of intracellular active oxygen. In addition, experiments will be performed to isolate and identify proteins present in H. pylori broth culture supernatants which enhance gastric epithelial cell's susceptibility to active oxygen, and evaluate mechanisms by which they increase gastric cell injury from active oxygen. Studies will also evaluate the ability of H. pylori to enhance oxidative DNA damage and analyze the role of the protein kinase C signal transduction pathway, activated by H. pylori toxins, as one mechanism through which these toxic effects are mediated. Even though gastric cancer has been decreasing in this country over the last several decades, it is still a leading cause of cancer mortality in minority groups. The identification of H. pylori as the cause of idiopathic chronic gastritis and this organism's relationship to gastric cancer allows us a chance to elucidate the role of active oxygen and H. pylori in the development of gastric cancer.